Ultraviolet-treated riboflavin alleviates atopic dermatitis by inhibiting NLRP3 inflammasome activation and M1 macrophage polarization via histone lactylation

Atopic dermatitis (AD) is a chronic inflammatory skin disorder requiring improved therapeutic strategies. This study investigates the potential of ultraviolet (UV)-treated riboflavin in AD treatment. Using a MC903-induced mouse model, we demonstrate that topical UV-treated riboflavin significantly attenuates AD progression. Mechanistically, UV-treated riboflavin suppresses macrophage nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation by reducing histone H3 lysine 9 lactylation (H3K9la) on NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC) promoter, decreasing interleukin-1β (IL-1β) secretion and subsequent keratinocyte-derived thymic stromal lymphopoietin (TSLP) production. It also directly inhibits inflammatory cytokine expression in keratinocytes. NLRP3 activation in vivo partially reverses these effects, confirming the central role of NLRP3 inflammasome inhibition. Our findings reveal a novel epigenetic mechanism of UV-treated riboflavin in modulating immune responses in AD, highlighting its potential as a therapeutic strategy for inflammatory skin disorders.